The central research theme of the Translational Addiction Sciences Center (TASC) is that impulsivity and reactivity to drug-associated environmental cues (cue reactivity) that confer vulnerability to relapse are mechanistically-linked to disrupted serotonin (5-HT) signaling through the 5-HT2A receptor (5-HT2AR) and 5- HT2CR in prefrontal-striatal-thalamic circuitry. The combined analyses in Projects 1 and 2 will define the role of 5-HT2AR:5-HT2CR imbalance in this circuit as an integrating mechanism underlying these phenotypes and explore the behavioral value in pharmacologically normalizing function in this system. We propose that one means by which this occurs is through the re-establishment of excitatory/inhibitory tone in the corticostriatal circuitry. Preclinical data from our group support this hypothesis, however, as yet, the 5-HT2AR:5-HT2CR role in the human neurocircuitry of addictions has not been studied. The overall goal of Project 1 is to evaluate the 5-HT2AR:5-HT2CR imbalance in the functional circuitry and effective connectivity of the corticostriatal pathway that confers risk for relapse in cocaine-dependent subjects vs. non drug-using controls. Brain and behavioral responses to the 5-HT2AR antagonist mirtazapine will be compared between subjects who possess the Cys23Ser single nucleotide polymorphism (SNP) of the 5-HT2cR gene. The 5-HT2cR Cys23Ser SNP is thought to decrease protein function and we have shown that cocaine-dependent subjects carrying the 5-HT2cR Ser23 SNP display significantly higher cue reactivity. Our working hypothesis is that cocaine- dependent subjects who carry the less-functional 5-HT2cR SNP will have a greater brain response to mirtazapine during performance of impulsive action and cue reactivity tasks, as shown by regional activation and effective connectivity within the prefrontal-striatal-thalamic circuit. This overall hypothesis will be tested through three specific aims with an exploratory aim to examine interactions between glutamate receptor SNPs and brain activation after a 5-HT2AR antagonist. This project will parallel preclinical research to discover the nature of the 5-HT2AR:5-HT2CR imbalance at the neural level that drives these two phenotypes, and to demonstrate effective pharmacological strategies to restore balance and inhibit relapse. Given the importance of impulsivity and cue reactivity In the risk for initiation and persistence of drug use as well as relapse to addiction, the outcomes of these studies will contribute to, a greater appreciation of the serotonergic neurobiology underlying these constructs and conceptually direct the next generation of pharmacotherapy discovery and development for addiction.